isotretinoin and Metaplasia

Clinical chemoprevention trials seek to intervene in the carcinogenic process to suppress, reverse, or delay the development of invasive cancer. Dysregulated cell growth is a hallmark of epithelial carcinogenesis, and proliferating cell nuclear antigen (PCNA) is a marker of dysregulated proliferation that is highly expressed in non-small cell lung cancers. Squamous metaplasia of the bronchial epithelium is found in chronic smokers and has been considered an early premalignant change. To evaluate the effect of 13-cis-retinoic acid (13-cRA) on PCNA modulation, we evaluated PCNA expression in a total of 706 bronchial biopsy specimens from histologically normal, hyperplastic, metaplastic, and dysplastic bronchial tissues obtained from 86 healthy smokers at baseline, of whom 69 subjects had completed 6 months of treatment on a randomized placebo-controlled chemoprevention trial of 13-cRA and had repeat bronchoscopic biopsies. PCNA expression was evaluated with respect to bronchial metaplasia and as an intermediate end point for response in the trial. In the bronchial biopsies obtained from six standardized pretreatment and posttreatment sites, high PCNA expression correlated significantly with more advanced histological grade (P < 0.001). Furthermore, smoking cessation during therapy correlated well with reduced PCNA expression (P = 0.006), although multivariate analysis indicated that this reduction in PCNA expression was associated with the reversal of squamous metaplasia. The level of PCNA expression appeared to correlate with the level of epidermal growth factor receptor expression both at baseline and at 6 months. In those patients who ceased smoking during the intervention, the 13-cRA also appeared to be more effective than placebo in reducing PCNA expression (P = 0.034 in all of the layers; P = 0.026 in basal layers). The efficacy of 13-cRA in the down-regulation of PCNA in quitters was independent of baseline PCNA expression levels. Our study demonstrated that increased PCNA expression was associated with histological progression from normal bronchial epithelium to squamous metaplasia and dysplasia. The modulation of PCNA by 13-cRA in patients who quit smoking suggests a potentially important role for regulating this proliferation marker in retinoid chemoprevention studies of former smokers.

Topics: Adult; Aged; Biomarkers; Biopsy; Cell Division; Cell Transformation, Neoplastic; Epithelium; Female; Humans; Isotretinoin; Lung; Lung Neoplasms; Male; Metaplasia; Middle Aged; Proliferating Cell Nuclear Antigen; Smoking; Smoking Cessation

This study of the effect of 13-cis-retinoic acid on serum levels of retinol was a laboratory correlate of a clinical chemoprevention trial in asymptomatic chronic smokers. All study participants had squamous metaplasia of the bronchial epithelium and received 6 months' treatment of either 13-cis-retinoic acid (1 mg/kg/day) or placebo. Baseline serum retinol levels were compared with levels taken immediately post-treatment. The placebo group (N = 38) had little change, whereas the 13-cis-retinoic acid group, (N = 35) experienced a decline in retinol levels (p = 0.06). Within the 13-cis-retinoic acid group, women's (N = 13) mean serum retinol levels dropped significantly, from 531 +/- 191 ng/ml (baseline) to 436 +/- 115 ng/ml (post-treatment) (p = 0.03); men's (N = 22) levels virtually did not change (p = 0.43). Therefore, the borderline-significant overall decline in the 13-cis-retinoic acid group was due entirely to the decline among women subjects. The etiology of this effect is unknown. Our results suggest that chronic 13-cis-retinoic acid administration may lead to a clinically significant reduction in serum retinol levels in females. This finding may have implications for currently ongoing chemoprevention trials that administer 13-cis-retinoic acid for 3 years.

Topics: Adult; Anticarcinogenic Agents; Bronchi; Female; Humans; Isotretinoin; Lung Neoplasms; Male; Metaplasia; Middle Aged; Smoking; Vitamin A

Retinoids have proven chemopreventive efficacy in both preclinical and clinical studies. This trial was designed to confirm the finding of an earlier uncontrolled trial that the synthetic retinoid etretinate had major activity in reversing squamous metaplasia found in the bronchial epithelium of chronic smokers.. We prospectively evaluated 152 smokers with bronchoscopy and obtained biopsies from six sites. Subjects with dysplasia and/or a metaplasia index of greater than 15% were randomly assigned to receive either 1 mg/kg isotretinoin or placebo daily for 6 months. Of 86 subjects randomized (41 isotretinoin, 45 placebo), 69 were reevaluated at the completion of treatment.. In the group as a whole, the metaplasia index decreased over time from a mean +/- SE of 35.8% +/- 2.7% at baseline to 28.1% +/- 3.3% at the completion of treatment (P = .01) by repeated measures analysis of variance [ANOVA]); a reduction in the metaplasia index (> 8%) was noted in both isotretinoin and placebo groups (19 of 35 [54.3%] and 20 of 34 [58.8%], respectively). Complete reversal of squamous metaplasia was noted in nine subjects from each group. However, the magnitudes of the mean metaplasia index changes did not differ significantly in the two treatment groups. In both groups, smoking cessation resulted in significant declines in the extent of squamous metaplasia, whereas no significant change in metaplasia index was found among those who continued to smoke.. Squamous metaplasia was frequently observed in bronchial biopsy samples from chronic smokers. From this study, we conclude that isotretinoin has no effect on squamous metaplasia, a potential intermediate end point of bronchial carcinogenesis. Although determining the exact role of isotretinoin in lung cancer prevention requires further study, the finding that there was a significant decrease in squamous metaplasia in the placebo group emphasizes the critical importance of a placebo-controlled study design in chemoprevention trials using intermediate end points.

Topics: Adult; Aged; Bronchi; Epithelium; Female; Humans; Infant, Newborn; Isotretinoin; Lung Neoplasms; Male; Metaplasia; Middle Aged; Placebos; Precancerous Conditions; Regression Analysis; Smoking

The cellular and molecular basis of metaplasia and declining neurogenesis in the aging olfactory epithelium (OE) remains unknown. The horizontal basal cell (HBC) is a dormant tissue-specific stem cell presumed to only be forced into self-renewal and differentiation by injury. Here we analyze male and female mice and show that HBCs also are activated with increasing age as well as non-cell-autonomously by increased expression of the retinoic acid-degrading enzyme CYP26B1. Activating stimuli induce HBCs throughout OE to acquire a rounded morphology and express IP3R3, which is an inositol-1,4,5-trisphosphate receptor constitutively expressed in stem cells of the adjacent respiratory epithelium. Odor/air stimulates CYP26B1 expression in olfactory sensory neurons mainly located in the dorsomedial OE, which is spatially inverse to ventrolateral constitutive expression of the retinoic acid-synthesizing enzyme (RALDH1) in supporting cells. In ventrolateral OE, HBCs express low p63 levels and preferentially differentiate instead of self-renewing when activated. When activated by chronic CYP26B1 expression, repeated injury, or old age, ventrolateral HBCs diminish in number and generate a novel type of metaplastic respiratory cell that is RALDH

Topics: Aging; Animals; Female; Isotretinoin; Male; Metaplasia; Mice; Neural Stem Cells; Neurogenesis; Olfactory Mucosa; Olfactory Receptor Neurons; Retinoic Acid 4-Hydroxylase

N-(all-trans-Retinoyl)amino acids were synthesized via all-trans-retinoyl chloride and an ester of the amino acid. The retinoyl derivatives of leucine, phenylalanine, alanine, tyrosine, and glutamic acid were prepared. The 13-cis-retinoyl derivatives of leucine, phenylalanine, alanine, and glycine were prepared similarly from 13-cis-retinoic acid. In assays of the retinoylamino acids for reversal of squamous metaplasia in hamster trachea organ cultures, these compounds were less active than retinoic acid, but the leucine, alanine, and phenylalanine derivatives were similar in activity to several retinamides that suppress bladder carcinogenesis in vivo. Two of the retinoylamino acids, as well as two simple retinamides, were shown to be moderately cytotoxic to murine leukemia and human epidermoid carcinoma cells in culture.

Topics: Amino Acids; Animals; Cricetinae; Indicators and Reagents; Metaplasia; Organ Culture Techniques; Retinoids; Structure-Activity Relationship; Trachea